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Plasma Proteomics Identifies a Chemokine Storm in Idiopathic

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Plasma Proteomics Identifies a Chemokine Storm in Idiopathic Received: 6 April 2018 | Revised: 12 April 2018 | Accepted: 17 April 2018 DOI: 10.1002/ajh.25123 RESEARCH ARTICLE AJH Plasma proteomics identifies a ‘chemokine storm’ in idiopathic multicentric Castleman disease Sheila K. Pierson1 | Aaron J. Stonestrom2 | Dustin Shilling1 | Jason Ruth3 | Christopher S. Nabel3 | Amrit Singh4 | Yue Ren1 | Katie Stone5 | Hongzhe Li1 | Frits van Rhee5 | David C. Fajgenbaum1 1 University of Pennsylvania, Philadelphia, Human Herpesvirus-8 (HHV-8)-negative/idiopathic multicentric Castleman disease (iMCD) is a Pennsylvania; 2Hospital of the University of poorly understood disease involving polyclonal lymphoproliferation with dysmorphic germinal cen- Pennsylvania, Philadelphia, Pennsylvania; 3Castleman Disease Collaborative Network, ters, constitutional symptoms, and multi-organ failure. Patients can experience thrombocytopenia, Boston, Massachusetts; 4University of anasarca, reticulin fibrosis, renal dysfunction, organomegaly, and normal immunoglobulin levels, – British Columbia, Vancouver, Canada; iMCD-TAFRO. Others experience thrombocytosis, milder effusions, and hypergammaglobulinemia, 5University of Arkansas for Medical – Sciences, Little Rock, Arkansas iMCD-Not Otherwise Specified (iMCD-NOS). Though the etiology is unknown in both subtypes, iMCD symptoms and disease progression are believed to be driven by a cytokine storm, often Correspondence including interleukin-6 (IL-6). However, approximately two-thirds of patients do not respond to David C. Fajgenbaum, Hospital of the anti-IL-6 therapy; alternative drivers and signaling pathways are not known for anti-IL-6 nonres- University of Pennsylvania, 3400 Spruce St, S05094 Silverstein, Division of ponders. To identify potential mediators of iMCD pathogenesis, we quantified 1129 proteins in 13 Translational Medicine and Human plasma samples from six iMCD patients during flare and remission. The acute phase reactant NPS- Genetics, Philadelphia, PA, 19104. PLA2 was the only significantly increased protein (P 5 .017); chemokines and complement were Email: [email protected] significantly enriched pathways. Chemokines represented the greatest proportion of upregulated cytokines, suggesting that iMCD involves a chemokine storm. The chemokine CXCL13, which is essential in homing B cells to germinal centers, was the most upregulated cytokine across all patients (log2 fold-change 5 3.22). Expression of CXCL13 was also significantly increased in iMCD lymph node germinal centers compared to controls in a stromal meshwork pattern. We observed distinct proteomic profiles between the two iMCD-TAFRO patients, who both failed anti-IL-6- therapy, and the four iMCD-NOS patients, in whom all three treated with anti-IL-6-therapy responded, suggesting that differing mechanisms may exist. This study reveals proteomic differen- ces between flare and remission and the potential to molecularly define iMCD subgroups. 1 | INTRODUCTION Recently, a new clinical subtype of iMCD has been described involving thrombocytopenia, anasarca, fibrosis of bone marrow, renal Human Herpesvirus (HHV)-8-negative, idiopathic multicentric Castle- dysfunction, organomegaly (iMCD-TAFRO), and normal immunoglobu- man disease (iMCD) is a polyclonal lymphoproliferative disorder with lin levels.6,7 Other iMCD patients, who do not have TAFRO features an unknown etiology. Approximately 1000 individuals of all ages are (herein referred to as iMCD-Not Otherwise Specified or iMCD-NOS), diagnosed with iMCD each year in the USA,1 and 35%-45% of patients more often demonstrate thrombocytosis, hypergammaglobulinemia, die within 5 years of diagnosis.2–4 Patients experience heterogeneous and less severe fluid accumulation.8 clinical and laboratory abnormalities including constitutional symptoms, Similar clinical and histopathological changes that occur in iMCD anemia, anasarca, renal failure, hypoalbuminemia, thrombocytopenia or also occur in HHV-8-positive MCD in which the HHV-8 virus replicates thrombocytosis, and multicentric lymphadenopathy. Characteristic his- in lymph node plasmablasts and initiates a cytokine storm driving poly- topathological features of the enlarged lymph nodes include dysmor- clonal lymphoproliferation and systemic symptoms.9 Likewise, a cyto- phic (atrophic or hyperplastic) germinal centers, hypervascularization, kine storm—the uncontrolled release of proinflammatory cytokines10— polyclonal lymphoproliferation, and/or polytypic plasmacytosis.5 is presumed to drive iMCD pathogenesis. However, the etiology, Am J Hematol. 2018;1–11. wileyonlinelibrary.com/journal/ajh VC 2018 Wiley Periodicals, Inc. | 1 2 | AJH PIERSON ET AL. signaling pathways, dysregulated cell types, and composition of the IL-6-therapy (siltuximab or tocilizumab) during their disease course cytokine storm, including the various families of cytokines, such as (Supporting Information Table S2). Of those treated, patients 1–3 interleukins and chemokines, are not known in iMCD. Chemokines reg- responded to treatment and patients 5–6 did not respond. At the time ulate leukocyte migration, lymphoid tissue organization, innate and of flare sample collection, patients 5 and 6 (flare 1) were on anti-IL-6 adaptive immunity, angiogenesis, and immune system development, therapy, and at the time of remission sample collection, patients 1, 2, 3, whereas interleukins are often involved in stimulating immune and 5 were on anti-IL-6 therapy. Complete treatment information is responses, such as inflammation. listed in Supporting Information Table S2. Plasma was isolated follow- Several lines of evidence suggest that excess interleukin-6 (IL-6), a ing standard protocols, stored at 2808C, and shipped in 150 mL ali- cytokine that promotes B cell and plasma cell growth, plays an impor- quots overnight on dry-ice to SomaLogic, Inc (Boulder, Colorado) for tant role in symptoms and disease progression in many iMCD analysis. patients.11,12 Anti-IL-6 monoclonal antibodies (mAb) tocilizumab (anti- IL-6 receptor) and siltuximab (anti-IL-6) have been approved for iMCD 2.2 | High-throughput protein quantification and 5,13,14 in various regions of the world. However, approximately two- analysis thirds of iMCD patients did not respond to IL-6 blockade with siltuxi- ’ mab in the registrational trial,14 and, of the 35 siltuximab nonrespond- SomaLogic s SOMAscan®, a multiplexed, aptamer-based binding-assay, 17 ers in the study, more than one-half had normal IL-6 levels during which has been described in depth previously, was used to quantify active disease (<5pg/mL).12 In agreement, a recent study of serum the relative levels of 1129 proteins. Briefly, the SOMAscan assay uses cytokines found that more than one-half of the 17 iMCD patients Slow-Off-rate Modified Aptamer (SOMAmer) reagents, which are examined had undetectable IL-6 levels during flare.15 These results sug- chemically modified nucleotides, to bind and quantify target proteins in gest that IL-6 independent pathways may be driving disease pathoge- relative fluorescent units directly proportional to the amount of target nesis in a portion of iMCD patients. Current treatment options for protein in the sample. 18 these patients include corticosteroids, rituximab, and cytotoxic chemo- Data analyses were performed using R version 3.4.2. Data were therapies, which have limited efficacy and significant toxicity in normalized by log2 transformation. Fold-change was calculated as the iMCD.16 Efforts to identify new treatment strategies for patients who log2 (flare/remission) for each patient. Both of the patient 6 flare sam- do not respond to anti-IL-6 therapy are limited by a poor understand- ples, labeled as 6.1 and 6.2, were compared to the remission sample. ing of iMCD pathogenesis. Protein function was assigned according to the UniProt molecular func- Here, we performed for the first time unbiased, systematic quanti- tion annotation. For comparison of flare and remission and of clinical fication of plasma proteins in six iMCD patients’ matched flare and subgroups, P values were calculated using Linear Models for Microarray 19 remission samples using SomaLogic SOMAscan® to generate insights and RNA-Seq data (LIMMA) and adjustment for multiple-hypothesis into iMCD pathogenesis. testing was performed using the method of Benjamini and Hochberg (false discovery rate (FDR) < .05).20 2 | METHODS Gene-set enrichment analyses based on the Reactome Pathway Database and Kyoto Encyclopedia of Genes and Genomes (KEGG) 2.1 | Patients and sample collection database and drug enrichment analysis based on the Library of Inte- grated Network-Based Cellular Signatures (LINCS) 1000 database were All patients consented to the research, which was approved by the Uni- performed using Enrichr.21,22 The LINCS 1000 database was used to versity of Arkansas for Medical Sciences Institutional Review Board. identify compounds that decrease gene expression of upregulated pro- Clinical data were collected as part of routine care. Between 2007 and teins. Ingenuity® Pathway Analysis (IPA) software was used for gene- 2016, peripheral blood samples were collected from six patients whose set enrichment and pathway analyses. Enriched gene-sets identified diagnoses are consistent with the iMCD diagnostic criteria.5 One sam- among upregulated and/or downregulated proteins were compared ple during flare (defined as C-Reactive Protein (CRP) > 10 mg/L and against enriched gene-sets identified among the background of 1129 the presence of at least two iMCD-related minor diagnostic criteria5) quantified proteins for all gene-set
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